DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) The long term goal of this project is to determine the mechanisms by which the bronchial circulation attenuates the increased pulmonary vascular permeability cause by ischemia-reperfusion (IR) injury in isolated sheep lungs. Based on preliminary data, it is hypothesized that the protective effect results from perfusion of the pulmonary vascular vasa vasorum by the bronchial circulation. Perfusion of pulmonary vasa vasorum could protect by delivering metabolic substrates and antioxidants, removing toxic metabolites or stimulating the release of protective factors within pulmonary vessels.One such protective factor may be nitric oxide (NO). Specific Aim 1 proposes to characterize the morphology and hemodynamics of pulmonary vasa vasorum. To confirm that bronchial arterial (BA) blood flow prevents changes in pulmonary vascular permeability via vasa vasorum perfusion, it will be determine if the increased permeability caused by IR injury and the protection conferred by BA perfusion occur in extraalveolar vessels supplied by vasa vasorum. Specific Aim 2 proposes to determine if a protective effect of BA perfusion during pulmonary ischemia without reperfusion is mediated by vasa vasorum perfusion or bronchopulmonary anastomotic flow. Specific Aim 3 will determine if the protective effect of vasa vasorum perfusion is dependent on perfusate characteristics, such as contents of oxygen, glucose, albumin, and erythrocytes or perfusate flow. To determine if vasa vasorum flow protects via generation of NO, inhibitors of NO synthesis and NO donor compounds will be used to block and mimic, respectively, the protective effect of vasa vasorum perfusion. The separate effects of IR injury on bronchial and pulmonary vessels will be examined by comparing measurements of vascular permeability and NO production in both circulations after variable lengths of ischemia and reperfusion. These results may provide new information about the physiology and function of pulmonary vasa vasorum and could have implications with respect to clinical conditions where vasa vasorum flow is reduced, such as lung transplantation.